Project Summary/Abstract Millions of concussions occur annually in the US and are currently diagnosed and managed based on clinical judgment, which is largely informed by a patient?s self-report of symptoms. There is a great need to identify objective biomarkers to augment current clinical tools for diagnosing concussion and identifying patients at risk for prolonged recovery. The objectives of this proposal are to determine the effects of concussion on blood markers of inflammation and establish if these markers can help discriminate concussed individuals from controls and predict prolonged recovery following concussion. The central hypotheses are 1) that an early-acute post- injury increase in inflammatory markers will improve the discrimination of concussed individuals from controls relative to traditional brain injury markers, and 2) post-injury inflammatory markers will predict the time course of clinical and neurophysiological recovery following concussion. To test our hypotheses, we will leverage collected biospecimens and data from the NCAA-DoD Concussion Assessment, Research and Education (CARE) Consortium Study, a large, prospective study investigating the natural history of concussion in NCAA student- athletes and military service academy cadets. Peripheral levels of inflammatory markers selected based on our preliminary data will be quantified from existing aliquots of serum in CARE athletes and cadets with concussion at pre-injury visits and several post-injury visits. CARE post-injury visits include two acute time points (i.e., within 6-hours and 24-48 hours post-injury), the point at which individuals no longer report symptoms, and seven days following return-to-play. Matched contact sport athletes, non-contact sport athletes, and cadets complete similar visits and will serve as controls. Analyses will incorporate existing clinical, neuroimaging, and brain injury blood biomarker data. We will address the following specific aims: Aim 1) Prospectively characterize the time course of changes in peripheral markers of inflammation from pre- to post-concussion in athletes and cadets relative to non-injured controls, Aim 2) Determine the extent to which peripheral inflammatory markers are associated with symptom and neuroimaging-related indices of recovery following concussion in athletes and MSA members. Exploratory hypotheses will determine the potential moderating effects of sex and sex hormones on these markers and outcomes. This work is significant because it will prospectively determine the effects of concussion on blood markers of inflammation in a large, extensively characterized cohort of men and women athletes and cadets. This work will also determine the utility of blood-based inflammatory markers as complementary diagnostic and prognostic markers for concussion to be used in conjunction with brain injury markers and other clinical measures.